This invention relates to a method of using a drug to reduce and prevent two very serious problems that often arise as a result of surgery involving cardiopulmonary bypass.
As indicated by the name, "cardiopulmonary bypass" (abbreviated as CPB, and also referred to herein simply as "bypass") involves circulatory bypass of the heart and the lungs, during certain types of surgery. CPB is most commonly used in the following types of surgery:
(1) surgery to repair occluded (blocked or clogged) coronary arteries which cannot be adequately reopened by less invasive techniques such as balloon angioplasty; this type of surgery is often referred to as "coronary artery bypass grafting" (CABG) surgery; PA0 (2) repair of heart valves (as used herein, this phrase includes replacing a native heart valve with a replacement valve, which can be completely mechanical or which may contain tissue, such as heart valves harvested from pigs or human cadavers and treated to reduce their antigenicity); PA0 (3) surgical correction of cardiac arrhythmias, such as surgery to remove or ablate (using microwave radiation or other forms of treatment) segments of heart tissue that create "short circuits" that cause or aggravate irregularities in the heartbeat; PA0 (4) removal of heart muscle tissue to increase contact between a ventricular wall and oxygenated blood, as has recently been developed using laser devices; PA0 (5) heart transplant surgery; PA0 (6) lung transplant surgery; and, PA0 (7) surgery to correct a congenital heart disease, which is done most commonly in children. It should be noted that children who suffer from congenital heart disease that is sufficiently severe to require CPB surgery also tend to suffer from high rates of pulmonary hypertension. PA0 1. "cardiac output" (abbreviated as CO), which measures how many liters of blood are pumped by the heart per minute. PA0 2. "cardiac index" (CI), which is cardiac output (liters of blood pumped per minute), divided by the body surface area of the patient, to make these values more comparable between patients of varying sizes and weights. PA0 3. "left ventricular stroke work index" (LVSWI), which measures how much pumping work a left ventricle does during each heartbeat. This quantity is divided by the surface area of a patient's body, to make LVSWI values comparable between patients of varying sizes and weights. PA0 4. "pulmonary artery wedge pressure" (PAWP) values. If these values increase to abnormal levels, they indicate that the left side of the heart is unable to function properly.
All of these types of surgery are described in various well-known medical texts, such as Gibbon's Surgery of the Chest (Sabiston and Spencer, eds., Saunders Publ., Philadelphia, Pa.) and in various medical journals that are devoted to the subject of cardiac and/or thoracic surgery.
During surgery that involves CPB, the heart is usually stopped from beating while it and/or the lungs are being worked on. The most common and obvious reason for temporarily stopping the heart is so that the surgeons will not have to perform delicate surgery on a "moving target". Normally, the heartbeat is stopped by the combined effects of 3 steps: (1) perfusing the heart with a liquid called "cardioplegia" solution, which contains a sufficient quantity of potassium to interfere with the cellular electrochemical interactions that initiate and control each heart contraction; (2) chilling the heart, by means such as pouring ice-cold saline slush directly onto it and allowing the cold slush to remain in contact with the heart, in a basin that is formed when the pericardial sac is cut open to expose the heart; and (3) clamping the aorta shut, so that the left ventricle cannot pump blood anywhere.
While the heart is not beating, most of the patient's body (excluding the heart and, to some extent, the lungs) are supported by a bypass machine (also called a CPB machine, or a heart-lung machine). This machine receives deoxygenated blood from the patient's body, adds oxygen and various nutrients to the blood, and pumps the oxygenated blood back into the patient's body, excluding the heart.
During bypass, the body and brain are cooled several degrees, to reduce the need of brain cells and other cells for oxygen and nutrients. The heart muscle must be chilled to a substantially colder temperature, since (in most operations) the heart receives no oxygenated blood whatever from the bypass machine.
While a patient is on bypass, the heart suffers from a condition called "ischemia". Ischemia refers to inadequate blood supply to an organ, or a portion thereof. Since blood is the only source of oxygen and nutrients for cells and tissue, ischemia imposes a major stress on cells and tissues. This is especially true for the heart and brain, which are much more vulnerable to ischemic damage than any other organs, because of various physiological factors. If ischemia persists in either of these organs for more than a few minutes without chilling the organ, severe metabolic derangement can begin to occur, and it can lead quickly to large-scale cell death, and to tissue death ("infarction") which can rapidly become lethal to the patient.
In addition, it should also be noted that when a ischemic organ's blood supply is re-established, the damage in the organ often increases, due to the formation of "free radical" compounds, catalyzed by enzymes such as xanthin oxidase. These highly reactive molecules will attack nearly any type of biomolecule, and can severely damage and rupture cell membranes in ischemic tissue shortly after it is resupplied with oxygen.
After the surgical work requiring bypass is completed, the surgeons flush out the potassium-containing cardioplegia liquid from the heart, and rewarm the heart muscle by passing warm blood or other liquid through the coronary arteries and veins. As the heart warms up, it usually begins to fibrillate, and the surgeons use electrodes to defibrillate the heart and restart the heartbeat.
When surgeons try to restart the heart after a period of bypass, the ischemic insult/damage to the heart muscle may be manifested in various ways. In almost all cases, at least some aberrations (including cardiac arrhythmias, abnormally rapid or slow heartbeat, ventricular fibrillation, or diminished pumping capacity) are likely to arise in varying degrees. These aberrations in heart performance, triggered by the ischemic and surgical insults to the heart, can trigger various complex interactions with and within the heart tissue that is still trying to recover from the ischemic period, in ways that tend to further complicate and aggravate hemodynamic (blood circulation) insufficiency during the period shortly after surgery.
To help understand the very complex challenge facing patients and surgeons involved in these procedures, it should be kept in mind that open-chest surgery is not done on healthy and vigorous patients with enough reserve capacity to help them withstand a major assault. Instead, it is almost always done on badly-weakened patients who have been struggling with serious heart problems for years, and whose health has slowly deteriorated to a point where they can no longer lead even a semblance of normal life without a major, life-threatening surgical intervention.
With proper care, the cardiac pumping aberrations that usually arise when the heart is restarted after bypass usually diminish within a few hours or days, as the patient gradually recovers from the operation. Nevertheless, these abnormalities are themselves a form of stress, and they make it more difficult and time-consuming for a patient who has been through CPB surgery to fully recover. In addition, these aberrations never completely disappear in some patients. Those patients must live with such problems, as both a symptom and a source of stress on their hearts, for the rest of their lives, which are often seriously degraded and shortened by the lasting and lingering damage to their heart's ability to function and pump blood normally and properly.
In addition, in a substantial fraction of CPB operations, the heart fails to begin beating properly in response to normal stimuli, while the chest remains open and the patient is still on the operating table. This type of crisis immediately becomes an all-out emergency, and the surgeons must rapidly resort to more powerful (and potentially damaging) stimulant drugs, and to electrical stimulation of the heart using higher voltages. In some cases, temporary implantation of a left-ventricle assisting pump or an aortic balloon pump becomes necessary; either of these can help handle some of the pumping load while the heart tries to recover some of its strength, but such devices are accompanied by other problems.
These emergency measures, if required to overcome a life-threatening crisis, impose even more stress on the patient's heart and body, and if these measures don't succeed quickly, the patient may die or suffer severe and permanent brain damage, comparable to a massive stroke.